title: Highly penetrative, drug-loaded nanocarriers improve treatment of glioblastoma.
abstract: Current therapy for glioblastoma multiforme is insufficient, with nearly universal recurrence. Available drug therapies are unsuccessful because they fail to penetrate through the region of the brain containing tumor cells and they fail to kill the cells most responsible for tumor development and therapy resistance, brain cancer stem cells (BCSCs). To address these challenges, we combined two major advances in technology: (i) brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery and (ii) repurposed compounds, previously used in Food and Drug Administration-approved products, which were identified through library screening to target BCSCs. Using fluorescence imaging and positron emission tomography, we demonstrate that brain-penetrating nanoparticles can be delivered to large intracranial volumes in both rats and pigs. We identified several agents (from Food and Drug Administration-approved products) that potently inhibit proliferation and self-renewal of BCSCs. When loaded into brain-penetrating nanoparticles and administered by convection-enhanced delivery, one of these agents, dithiazanine iodide, significantly increased survival in rats bearing BCSC-derived xenografts. This unique approach to controlled delivery in the brain should have a significant impact on treatment of glioblastoma multiforme and suggests previously undescribed routes for drug and gene delivery to treat other diseases of the central nervous system.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Jiangbing
authors.initials: J
authors.lastname: Zhou
authors.forename: Toral R
authors.initials: TR
authors.lastname: Patel
authors.forename: Rachael W
authors.initials: RW
authors.lastname: Sirianni
authors.forename: Garth
authors.initials: G
authors.lastname: Strohbehn
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.forename: Nha
authors.initials: N
authors.lastname: Duong
authors.forename: Thomas
authors.initials: T
authors.lastname: Schafbauer
authors.forename: Anita J
authors.initials: AJ
authors.lastname: Huttner
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: David J
authors.initials: DJ
authors.lastname: Sullivan
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Piepmeier
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004225:Dithiazanine / Q000008:administration & dosage / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods*; D005453:Fluorescence; D005909:Glioblastoma / Q000188:drug therapy*; D053208:Kaplan-Meier Estimate; D053758:Nanoparticles / Q000008:administration & dosage*; D049268:Positron-Emission Tomography; D051381:Rats; D013552:Swine
chemical_list: D000970:Antineoplastic Agents; D004225:Dithiazanine